Prostate cancer: a model of integration of genomic and non-genomic effects of the androgen receptor in cell lines model

Year: 2008

Authors: Bonaccorsi L., Nosi D., Quercioli F., Formigli L., Zecchi S., Maggi M., Forti G., Baldi E.

Autors Affiliation: Department of Clinical Physiopathology, Andrology Unit, Viale Pieraccini 6, I-50139 Florence, Italy;
Department of Anatomy, Histology & Forensic Medicine, University of Florence, Italy;
Institute for Complex Systems, National Research Council, Sesto Fiorentino, Firenze, Italy

Abstract: Androgens and the androgen receptor (AR) are involved both in early tumorigenesis of prostate cancer (PCa) and in androgen-refractory disease. The role of AR signalling has also been highlighted by the fusion gene TMPRSS2:ERG recently identified in the majority of PCa. Several data indicate that re-expression of AR in PCa cell lines confers a less aggressive phenotype. We observed that re-expression of AR in the AR-negative cells PC3 decreases anchorage-independent growth and Matrigel invasiveness of PC3-AR cells where plasma membrane interaction between AR and EGFR led to an interference with downstream signalling and internalization of activated EGFR. Our data evidenced a shift of EGFR internalization pathway from the clathrin-coated pit one mediating signalling and recycling of EGFR to the lipid raft-mediated one mainly involved in lysosomal degradation of EGFR. These effects involved an altered recruitment to EGFR of the adaptor proteins Grb2 and c-Cbl followed by a reduced ubiquitination of EGFR. Our preliminary results suggest that in PC3AR cells a pool of classical AR is located within cholesterol-rich membrane microdomains (namely as lipid rafts) and a population of EGFR is within cholesterol-rich membrane microdomains too. However, AR and EGFR membrane interaction that is increased by rapid androgen signalling is not within cholesterol-rich membrane microdomains. Our data enlighten that the crosstalk between genotropic and non-genotropic AR signalling interferes with signalling of EGFR in response to ligand leading to a lower invasive phenotype of AR-positive PCa cells. (c) 2008 Elsevier Inc. All rights reserved.

Journal/Review: STEROIDS

Volume: 73 (9-10)      Pages from: 1030  to: 1037

More Information: This work was supported by grants from Ministero dell’Università e della Ricerca Scientifica (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, PRIN2006, coordinator Prof. Gianni Forti), Ente Cassa di Risparmio di Firenze, Ministry of University, University of Florence.
KeyWords: Adaptor protein; Androgen; Androgen receptor; Cbl protein; Clathrin; Epidermal growth factor receptor; Growth factor receptor bound protein 2; Matrigel, article; cancer cell culture; Cancer genetics; Cancer growth; Cancer invasion; Cancer model; Carcinogenesis; Cell membrane; Early cancer; Fusion gene; Genomics; Human; Lipid raft; Lysosome; Nonhuman; phenotype; prostate cancer; protein degradation; protein expression; protein localization; protein protein interaction; signal transduction; tmprss2 erg fusion gene; ubiquitination, Animals; Cell Line, Tumor; Cell Membrane; Cholesterol; Genome; Humans; Lysosomes; Male; Membrane Microdomains; Models, Biological; Phenotype; Prostatic Neoplasms; Receptor, Epidermal Growth Factor; Receptors, Androgen; Signal Transduction
DOI: 10.1016/j.steroids.2008.01.028

Citations: 29
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